In this study, we have shown that the infection of human macrophages with EPEC triggers an atypical caspase-4-dependent NLRP3 signaling pathway, which is distinct from that stimulated by LPS transfection or infection by non-pathogenic E. coli, and requires signaling downstream of the effector Tir delivered by the pathogen into host cells. This evidence concerns the gene CASP4 and infection.